Context Memantine is a low- to moderate-affinity, uncompetitive N-methyl-D-aspartate receptor antagonist. Controlled
trials have demonstrated the safety and efficacy of memantine monotherapy
for patients with moderate to severe Alzheimer disease (AD) but no controlled
trials of memantine in patients receiving a cholinesterase inhibitor have
been performed.
Objective To compare the efficacy and safety of memantine vs placebo in patients
with moderate to severe AD already receiving stable treatment with donepezil.
Design, Setting, and Participants A randomized, double-blind, placebo-controlled clinical trial of 404
patients with moderate to severe AD and Mini-Mental State Examination scores
of 5 to 14, who received stable doses of donepezil, conducted at 37 US sites
between June 11, 2001, and June 3, 2002. A total of 322 patients (80%) completed
the trial.
Interventions Participants were randomized to receive memantine (starting dose 5 mg/d,
increased to 20 mg/d, n = 203) or placebo (n = 201) for 24 weeks.
Main Outcome Measures Change from baseline on the Severe Impairment Battery (SIB), a measure
of cognition, and on a modified 19-item AD Cooperative Study–Activities
of Daily Living Inventory (ADCS-ADL19). Secondary outcomes included
a Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus),
the Neuropsychiatric Inventory, and the Behavioral Rating Scale for Geriatric
Patients (BGP Care Dependency Subscale).
Results The change in total mean (SE) scores favored memantine vs placebo treatment
for SIB (possible score range, 0-100), 0.9 (0.67) vs –2.5 (0.69), respectively
(P<.001); ADCS-ADL19 (possible score
range, 0-54), –2.0 (0.50) vs –3.4 (0.51), respectively (P = .03); and the CIBIC-Plus (possible score range, 1-7),
4.41 (0.074) vs 4.66 (0.075), respectively (P = .03).
All other secondary measures showed significant benefits of memantine treatment.
Treatment discontinuations because of adverse events for memantine vs placebo
were 15 (7.4%) vs 25 (12.4%), respectively.
Conclusions In patients with moderate to severe AD receiving stable doses of donepezil,
memantine resulted in significantly better outcomes than placebo on measures
of cognition, activities of daily living, global outcome, and behavior and
was well tolerated. These results, together with previous studies, suggest
that memantine represents a new approach for the treatment of patients with
moderate to severe AD.